Infantile Cerebellar-Retinal Degeneration

A number sign (#) is used with this entry because of evidence that infantile cerebellar-retinal degeneration (ICRD) is caused by homozygous or compound heterozygous mutation in the aconitase-2 gene (ACO2; 100850) on chromosome 22q13.

Description

Infantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012).

Clinical Features

Spiegel et al. (2012) reported 8 patients from 2 Arab Muslim families with a severe infantile-onset neurodegenerative disorder. The patients presented at age 2 to 6 months with truncal hypotonia, head bobbing, athetosis, generalized seizures, and ophthalmologic abnormalities that included strabismus, nystagmus, abnormal eye movements, and abnormal pursuit. The disease course was characterized by failure to thrive, muscle atrophy, and hypo-/areflexia. All failed to attain significant developmental milestones, culminating in profound psychomotor retardation. Only some achieved rolling, sitting, and recognition of family. There was progressive degeneration of vision, with retinal dystrophy and optic atrophy. Two patients had progressive hearing loss. EEG showed generalized or focal spike and wave activity and slow background compatible with a nonspecific encephalopathy. One patient had evidence of a peripheral demyelinating neuropathy. Brain MRI tended to be normal in the first months of life, but thereafter showed progressive cerebellar atrophy, cortical atrophy, and thinning of the corpus callosum. Extensive laboratory studies were normal, including mitochondrial respiratory enzyme activities on skeletal muscle, but there was a mild decrease in glutamate oxidation (about 63% of normal). The oldest living patient was 18 years old and in a vegetative state.

Metodiev et al. (2014) reported 2 infant brothers, born of consanguineous Algerian parents, with ICRD. Both presented at birth with episodes of central apnea and bradycardia; 1 also showed hypotonia, abnormal twisting of the arms, and abnormal eye movements. Both patients died in early infancy. One of the patients had edema of the optic discs without retinal anomalies, whereas the other had pallor of the optic discs with extinguished visual-evoked potentials and electroretinograms. Brain imaging of both patients showed moderate cerebellar atrophy. Laboratory investigations showed metabolic acidosis and hyperglycemia with normal serum lactate in 1 patient, but no metabolic abnormalities in the other. An unrelated 10-year-old girl had less severe manifestations of the disorder. She had severely delayed psychomotor development with profound intellectual disability and was wheelchair-bound. In infancy, she had nystagmus, poor eye contact, and progressive microcephaly. Fundus examination showed pallor of the optic discs with altered visual-evoked potentials. Brain MRI showed moderate cerebellar atrophy. Analysis of mitochondrial respiratory chain activities in skeletal muscle and fibroblasts was normal.

Inheritance

The transmission pattern of infantile cerebellar-retinal degeneration in the families reported by Spiegel et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By homozygosity mapping followed by exome sequencing of 2 families with infantile cerebellar-retinal degeneration, Spiegel et al. (2012) identified a homozygous mutation in the ACO2 gene (S112R; 100850.0001).

In 3 patients from 2 unrelated families with ICRD, Metodiev et al. (2014) identified homozygous or compound heterozygous mutations in the ACO2 gene (100850.0004-100850.0006). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. All mutant proteins failed to completely rescue respiratory growth defects in an aco1 (100880)-deficient yeast strain at 37 degrees Celsius, although there was variation in response to different temperatures. ACO1 activity was also reduced in patient cells.